The known processes for preparing simvastatin and derivatives thereof can basically be divided according to two synthesis approaches used, namely (a) the so-called re-esterification route and (b) the direct methylation of the methyl butyrate side chain.
An example for the first synthetic approach is described in EP-B-33 538. It discloses a five-step process which comprises the steps of (1) exhaustive saponification of lovastatin; (2) relactonisation; (3) selective silylation; (4) re-acylation; and (5) desilylation. The reported overall yields obtained by this process are low, namely just 48% (J. Org. Chem 56, 4929 (1991)). This is partly attributable to the low yield of 69% obtained in the selective silylation step (3). Further, the re-acylation (4) is carried out at a high temperature of 100.degree. C. for prolonged time (18-36 hours) in the presence of 4-pyrrolidino pyridine or dialkylamino pyridine. These reaction conditions lead to formation of a substantial amount of undesired by-product (unsaturated lactone) resulting from the elimination of the tert.-butyldimethylsilyloxy radical, present as protecting group of the alcohol, from the .delta.-valerolactone moiety. Finally, also large amounts of starting diol lactone and unconsumed acid chloride remain at the end of the reaction.
In EP-B-287340 an improved acylation process for the preparation of antihypercholesterolemic compounds is disclosed which comprises the combining of a suitable acid chloride with an alkali metal bromide, dialkylaminopyridine and a polyhydronaphthyl alcohol to obtain the corresponding acylated product. The reaction is carried out at a relatively high temperature of 70.degree. C. so the unsaturated lactone by-product is also formed in an amount of about 1-2%. Moreover, the preferred solvent used in this process is pyridine which is environment and people unfriendly.
The second synthesis approach, the direct alkylation of the methyl butyrate side chain, is disclosed in EP-B-137 445 and EP-B-299 656. The processes involve use of a metal alkyl amide and methyl halide. The main disadvantage of these processes is the contamination of the product by a significant amount of unconverted starting materials, e.g. lovastatin. Since simvastatin and lovastatin differ only by one methyl group, it is very difficult to isolate simvastatin from a mixture containing both by means of conventional separation methods. Thus, an additional purification step is normally required, for example the selective hydrolysis of residual lovastatin as per the method disclosed in WO 93/16188.
N-methylimidazole, also referred to as 1-methylimidazole, is a known compound useful for the acetylation of hydroxy compounds with acetic anhydride (see Anal. Chem. 50, 1542-1545 (1978)). However, the reaction with sterically hindered alcohols gives only a poor yield. In case of tert.-butyl alcohol the yield is only 36%.
Moreover, in Anal. Chem. 52, 572 (1980) it is described that N-methylimidazole can also be employed as a catalyst for the acetylation of hydoxyl-terminated polymers by acetic anhydride.